Two mechanisms were found for rendering T cell clones unresponsive vitro. One involved stimulation with antigen and antigen-presenting cells fixed with a chemical cross-linker. The other involved stimulation with antigen and Ia molecules in planar lipid membranes. In both systems the T cells were rendered incapable of producing interleukin 2 (IL-2) when subsequently challenged with antigen and normal antigen-presenting cells, although the cells did express low levels of IL-2 receptors and interleukin 3. The nonresponsiveness lasted at least 8 days, suggesting that both systems may be useful in vitro models for tolerance induction.